Pharmacogenomics and Translational Simulations to Bridge Indications for an Anti-Interferon-α Receptor Antibody
A type I interferon (IFN) gene signature shared by systemic lupus erythematous (SLE) and systemic sclerosis (SSc) was used to evaluate an anti‐type I IFN‐α receptor (IFN‐αR) monoclonal antibody, MEDI‐546, in a phase I trial in SSc. MEDI‐546 suppressed IFN signature in blood and skin of SSc patients...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2013-06, Vol.93 (6), p.483-492 |
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| creator | Wang, B Higgs, B W Chang, L Vainshtein, I Liu, Z Streicher, K Liang, M White, W I Yoo, S Richman, L Jallal, B Roskos, L Yao, Y |
| description | A type I interferon (IFN) gene signature shared by systemic lupus erythematous (SLE) and systemic sclerosis (SSc) was used to evaluate an anti‐type I IFN‐α receptor (IFN‐αR) monoclonal antibody, MEDI‐546, in a phase I trial in SSc. MEDI‐546 suppressed IFN signature in blood and skin of SSc patients in a dose‐dependent manner. To bridge clinical indications to SLE, we developed a model incorporating (i) pharmacokinetics (PK) and pharmacodynamics (PD) in SSc patients, (ii) internalization kinetics of MEDI‐546/IFN‐αR complex, and (iii) the different IFN signatures between SSc and SLE. Simulations predicted that i.v. administration of MEDI‐546 at 300‐ or 1,000‐mg monthly doses could suppress IFN signature in blood to levels of healthy subjects in 53 and 68% of SLE patients, respectively. An innovative approach utilizing a novel biomarker characterized the PD of MEDI‐546 by modeling and simulation and allowed rapid progression of MEDI‐546 from a phase I study in SSc to a randomized, multiple‐dose phase II trial.
Clinical Pharmacology & Therapeutics (2013); 93 6, 483–492. doi:10.1038/clpt.2013.35 |
| doi_str_mv | 10.1038/clpt.2013.35 |
| format | Article |
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Clinical Pharmacology & Therapeutics (2013); 93 6, 483–492. doi:10.1038/clpt.2013.35</description><subject>Adult</subject><subject>Aged</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - pharmacokinetics</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Biomarkers - blood</subject><subject>Biomarkers - metabolism</subject><subject>Clinical Trials, Phase II as Topic</subject><subject>Computer Simulation</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Humans</subject><subject>Interferon-alpha - genetics</subject><subject>Interferon-alpha - metabolism</subject><subject>Lupus Erythematosus, Systemic - drug therapy</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Pharmacogenetics</subject><subject>Pharmacology. 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Drug treatments</topic><topic>Receptor, Interferon alpha-beta - immunology</topic><topic>Receptor, Interferon alpha-beta - metabolism</topic><topic>Scleroderma, Systemic - blood</topic><topic>Scleroderma, Systemic - drug therapy</topic><topic>Scleroderma, Systemic - metabolism</topic><topic>Skin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, B</creatorcontrib><creatorcontrib>Higgs, B W</creatorcontrib><creatorcontrib>Chang, L</creatorcontrib><creatorcontrib>Vainshtein, I</creatorcontrib><creatorcontrib>Liu, Z</creatorcontrib><creatorcontrib>Streicher, K</creatorcontrib><creatorcontrib>Liang, M</creatorcontrib><creatorcontrib>White, W I</creatorcontrib><creatorcontrib>Yoo, S</creatorcontrib><creatorcontrib>Richman, L</creatorcontrib><creatorcontrib>Jallal, B</creatorcontrib><creatorcontrib>Roskos, L</creatorcontrib><creatorcontrib>Yao, Y</creatorcontrib><collection>Istex</collection><collection>Wiley Online Library Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, B</au><au>Higgs, B W</au><au>Chang, L</au><au>Vainshtein, I</au><au>Liu, Z</au><au>Streicher, K</au><au>Liang, M</au><au>White, W I</au><au>Yoo, S</au><au>Richman, L</au><au>Jallal, B</au><au>Roskos, L</au><au>Yao, Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacogenomics and Translational Simulations to Bridge Indications for an Anti-Interferon-α Receptor Antibody</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clinical Pharmacology & Therapeutics</addtitle><date>2013-06</date><risdate>2013</risdate><volume>93</volume><issue>6</issue><spage>483</spage><epage>492</epage><pages>483-492</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>A type I interferon (IFN) gene signature shared by systemic lupus erythematous (SLE) and systemic sclerosis (SSc) was used to evaluate an anti‐type I IFN‐α receptor (IFN‐αR) monoclonal antibody, MEDI‐546, in a phase I trial in SSc. MEDI‐546 suppressed IFN signature in blood and skin of SSc patients in a dose‐dependent manner. To bridge clinical indications to SLE, we developed a model incorporating (i) pharmacokinetics (PK) and pharmacodynamics (PD) in SSc patients, (ii) internalization kinetics of MEDI‐546/IFN‐αR complex, and (iii) the different IFN signatures between SSc and SLE. Simulations predicted that i.v. administration of MEDI‐546 at 300‐ or 1,000‐mg monthly doses could suppress IFN signature in blood to levels of healthy subjects in 53 and 68% of SLE patients, respectively. An innovative approach utilizing a novel biomarker characterized the PD of MEDI‐546 by modeling and simulation and allowed rapid progression of MEDI‐546 from a phase I study in SSc to a randomized, multiple‐dose phase II trial.
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| subjects | Adult Aged Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacokinetics Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - therapeutic use Biological and medical sciences Biomarkers - blood Biomarkers - metabolism Clinical Trials, Phase II as Topic Computer Simulation Dose-Response Relationship, Drug Female Humans Interferon-alpha - genetics Interferon-alpha - metabolism Lupus Erythematosus, Systemic - drug therapy Male Medical sciences Middle Aged Models, Biological Pharmacogenetics Pharmacology. Drug treatments Receptor, Interferon alpha-beta - immunology Receptor, Interferon alpha-beta - metabolism Scleroderma, Systemic - blood Scleroderma, Systemic - drug therapy Scleroderma, Systemic - metabolism Skin - metabolism |
| title | Pharmacogenomics and Translational Simulations to Bridge Indications for an Anti-Interferon-α Receptor Antibody |
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